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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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3.5. 1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives in Schedule 6 to restrict the use in cosmetic rinse-off and household cleaning preparations in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are:

  • Schedule 6 – New Entry
  • 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-C10-16 ACYL DERIVATIVES except:
  1. in cosmetic rinse-off preparations containing 7 per cent or less of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives when labelled the following statement:
  2. IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or

  3. in household cleaning preparations, other than those intended to be sprayed, containing 12 per cent or less of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives when labelled with the following statement:
  4. IF IN EYES WASH OUT IMMEDIATELY WITH WATER

  • Appendix E, Part 2 – New Entry
  • Standard Statement: E1 (If in eyes wash out immediately with water).
  • Appendix F, Part 3 – New Entry
  • Warning Statement: 79 (Will irritate eyes).
  • Safety Direction: 1 (Avoid contact with eyes).
  • The applicant's reasons for the request are:

    • 1-Deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives cause serious eye damage in in vivo tests with a GHS hazard classification of serious eye damage/eye irritation (Category 1) and a hazard statement of h518 – Causes serious eye damage.
    • 1-Deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives are used as a surfactant in rinse-off cosmetics at a concentration ≤ 7% and household cleaning products at a concentration ≤ 12%. Widespread and repeated public exposure is expected through the use of products containing the chemical. The finished products include cleansing products for skin/hair, laundry, dishwashing and hard surface cleaning.
    • The NICNAS assessment indicates that the hazard and risk characteristics of 1-deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives conform to the Scheduling Policy Framework factors for Schedule 6, specifically severe eye irritation in rabbits (corneal opacity not reversible in 21 days concurrent with conjunctival effects).
    • Irreversible eye damage or severe eye irritation can occur when consumers use products containing relatively high concentrations of 1-deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives, especially hair/skin cleansing products that may come into direct contact with the eyes.
    • Reasonably foreseeable harm to users can be reduced through strong label warnings and extensive safety directions. Setting a concentration cut-off for 1-deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives can protect consumers from serious eye damage.
    • An analogue of 1-deoxy-1-(methylamino)- d -glucitol N-C10-16 acyl derivatives (1-deoxy-1-(methylamino)- d -glucitol N-coco acyl derivatives, CAS No. 1591783-13-9), having very similar hazard, use and risk profiles, was recently scheduled in Schedule 6 of the Poisons Standard.
    Current scheduling status

    1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is not currently specifically scheduled in the Poisons Standard.

    1-Deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives, an analogue of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives, was recently considered for scheduling at the November 2016 Advisory Committee on Chemicals Scheduling (ACCS). The delegate's final decision for 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives, to be implemented on 1 February 2018, was to create a new Schedule 6 entry as follows:

    • Schedule 6
    • 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES except:
    1. in cosmetic rinse-off preparations containing 8 per cent or less of 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives when labelled the following statement:
    2. IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or

    3. in household cleaning preparations, other than those intended to be sprayed, containing 10 per cent or less of 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives when labelled with the following statement:
    4. IF IN EYES WASH OUT IMMEDIATELY WITH WATER.

  • Appendix E, Part 2 – New Entry
  • Standard Statement: E1 (if in eyes wash out immediately with water).
  • Appendix F, Part 3 – New Entry
  • Warning Statement: 79 (Will irritate eyes).
  • Safety Direction: 1 (Avoid contact with eyes).
  • Index – New Entry
  • 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL NCOCO ACYL DERIVATIVES
    cross reference: cocoyl methyl glucamaide
  • Schedule 6
    Appendix E, Part 2
    Appendix F, Part 3
  • Due to the similarity in chemical structure, hazard, use and risk profiles 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is captured by the above Schedule 6 entry for 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives :

    Comparison of similarity in chemical structure
    1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives

    Scheduling under consideration

    1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives

    Schedule 6

    chemical structure of 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives

    Major components: R = C11H23 (lauroyl methyl glucamide)
    R = C13H27 (myristoyl methyl glucamide)

    chemical structure of 1-deoxy-1-(methylamino)-D-glucitol <em>N</em>-coco acyl derivatives

    Where R = C7-C17 alkyl group or C17 alkenyl group

    Relevant scheduling history

    1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives has not been previously considered for scheduling. A scheduling history is therefore not available for 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives.

    An analogue of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives, 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives has been previously considered for scheduling as follows:

    Scheduling history of 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives

    At the November 2016 ACCS meeting the committee considered a proposal to schedule 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives. The committee recommended that based on the use of 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives as a surfactant, its severe eye irritancy and risk of spray products containing 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives entering the eye, that 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives be scheduled with exemptions and cut-off concentrations in cosmetic rinse-off preparations and household cleaning products. The delegate agreed however noting that a longer implementation time of 1 February 2018 would be required to allow for labelling changes and/or reformulation.

    Australian regulatory information

    1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives (lauroyl/myristoyl methyl glucamide) does not appear to be in any products on the ARTG.

    1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives (lauroyl/myristoyl methyl glucamide) is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

    International regulations

    The chemical was registered under REACH as of 6 July 2012. The registration dossier was updated on 17 April 2017, following compliance checks by ECHA.

    No known international restrictions or regulations have been identified by the applicant or the Secretariat.

    Substance summary
    Table 3.5.1: Chemical information for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives
    Property 1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives
    CAS number 173145-38-5
    Chemical structure chemical structure of

    Major components: R = C11H23 (lauroyl methyl glucamide)
    R = C13H27 (myristoyl methyl glucamide)

    IUPAC and/or common and/or other names

    D-glucitol, 1-deoxy-1-(methylamino)-, N-C10-16 acyl derivatives (CAS);

    Lauroyl/myristoyl methyl glucamide (INCI)

    C12-14 linear glucose amide; Lauryl methyl glucamide.

    The following information was extracted from the NICNAS assessment report for C12-14 Linear Glucose Amide and the NICNAS Existing Chemical secondary notification assessment report for d-glucitol, 1-deoxy-1-(methylamino)-, N-C10-16 acyl derivatives.

    Table 3.5.2: Acute toxicity end-points for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyls
    Toxicity Species 1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives SPF (2015) Classification
    Acute oral toxicity LD50 (mg/kg bw) Rat >2000 N/A
    Schedule 5
    Acute dermal toxicity LD50 (mg/kg bw) Rabbit >2000 Schedule 5
    Acute inhalational toxicity LC50 (mg/m3/4h) No data provided No data provided Schedule 5
    Skin irritation
    (human three application patch test)
    Rabbit
    Human
    Slight irritant Schedule 5
    Eye irritation Rabbit Slight irritating Schedule 6
    Skin sensitisation (Buehler) Guinea pig Not skin sensitising Schedule 5
    Acute toxicity

    Based on the studies provided, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives has a low acute oral and dermal toxicity (LD50 > 2000 mg/kg bw) in rats.

    Skin irritation

    1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is slightly irritating to rabbit skin, with Grade 1 erythema (two of three animals) and Grade 1 oedema (one of three animals) persisting for up to 7 days. The results do not warrant classification of the substance under the GHS.

    Eye irritation

    1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is a severe irritant to rabbit eyes in pure form, with vascularisation of the cornea observed in one out of the three animals tested. The irritation scores in this test could not be directly assessed against the GHS as the quantity instilled in the eyes was less than 10 mg, rather than the 100 mg required by the relevant Organisation for Economic Co-operation and Development (OECD) test guideline. The irritation scores were below the level for classification as an eye irritant, but instillation of larger quantities may have resulted in higher scores. Even at the lower quantity, the irritation was persistent, with effects seen in all animals at 4 days, and persisting up to 35 days in one animal. The results warrant the following classification of the substance under the GHS:

    Hazard classication and statement for eye irritations
    Hazard classification Hazard statement
    Serious eye damage/eye irritation (Category 1) h518 – Causes serious eye damage
    Sensitisation

    1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was not a skin sensitiser in guinea pigs using a modified Buehler test.

    Repeat-dose toxicity

    Based on the available information from studies in rats, repeated oral exposure to the substance is not considered to cause serious damage to health.

    • In a 28-day oral study in rats, a NOAEL of 100 mg/kg bw/day was established. At doses of 500 and 1000 mg/kg bw/day, a number of histological changes to the stomach lining were observed. Reduced food consumption and decreased bodyweight were also noted, along with a number of clinical chemistry changes that the study authors attributed to the poor nutritional status of these animals. Twelve of the twenty rats receiving 1000 mg/kg bw/day died or were sacrificed in extremis during the study. At the higher doses, breathing difficulties were also observed.
    • In a 13-week oral study in rats, breathing problems were observed in animals treated with 50 mg/kg bw/day and above. Clinical chemistry and haematology parameters were changed in animals treated with 200 and 500 mg/kg bw/day. These changes were considered to be due to the poor general condition of the animals. Six out of twenty animals treated with 500 mg/kg bw/day died of treatment-related causes during the study. No macroscopic or microscopic changes could be found during necropsy to explain the reasons for the deaths. On the basis of increased mortality and morbidity at 500 mg/kg bw/day, the study authors concluded that the NOAEL was 200 mg/kg bw/day in this study, as all findings at this dose were slight and there were no changes in blood or urinalysis parameters indicative of toxicity. However, based on clinical signs and the slight, transient effects on body weight gain at 200 mg/kg bw/day, a NOEL of 50 mg/kg bw/day was established.
    Mutagenicity

    1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives tested negative in two in vitro mutagenicity tests (Salmonella typhimurium reverse mutation assay and mouse lymphoma forward mutation assay) in the presence and absence of S9 metabolic activation. Positive results were observed in an in vitro study of chromosomal aberrations in Chinese hamster ovary (CHO) cells in the absence of metabolic activation, although the study authors concluded that the results were not biologically significant because of lack of reproducibility in repeat tests and because the values were within historical control ranges. This conclusion was supported by the negative genotoxicity results in an in vivo cytogenicity study in rat bone marrow cells.

    Carcinogenicity

    No information was provided.

    Reproduction and developmental toxicity

    In a one generation study in rats, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was not toxic to fertility or development. It caused adverse effects in parental animals on prolonged exposure to 350 mg/kg bw/day (reduction in body weight gains and in feed consumption in females).

    In a developmental toxicity study, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives did not cause developmental toxicity in rats at a dose where maternal toxicity was observed. The NOEL for developmental toxicity was determined to be 363 mg/kg bw/day (the highest dose tested) while the NOAEL for maternal toxicity was found to be 150 mg/kg bw/day based on decreased bodyweight gain at the higher dose.

    Observation in humans

    A three application patch test in human volunteers showed that 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was a mild skin irritant.

    Several skin irritation and sensitisation studies in humans have been performed using the C12 glucose amide component of 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives and formulations containing this component. However, the full details the formulation studies were not available. Consistent with the results of the animal studies for the substance, the C12 component was found to be a slight skin irritant under the conditions of the tests but was not a skin sensitiser.

    Public exposure

    The public exposure to 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is widespread and repeated. The principal route of exposure is dermal, while ocular exposure is highly possible. Based on current use proposals, the exposure to the substance is up to 7% concentration in rinse-off cosmetics for skin and hair cleansing and at up to 12% concentration in household cleaning products. As 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is classified as a Category 1 severe eye irritant at concentrations at or above 3%, without label warnings and appropriate directions, use of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives in consumer products at or above 3% could result in severe eye irritation to users. Setting a concentration cut-off for 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives used in cosmetics and household products, and providing users with labelling and first aid information could protect consumers.

    Pre-meeting public submissions

    Two (2) pre-meeting submission was received, one (1) that opposed the scheduling proposal for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives and one (1) that did not state their position.

    The main points were:
    • Scheduling of individual surfactants through the chemical scheduling process is out of step with international requirements for these substances and is unnecessary due to the well-established history of safe use of surfactant based products.
    • Recent advice from the committee on other surfactants (docusate sodium, sodium α-olefin sulfonates and sodium alkyl sulfates) indicate that "there is no evidence of a public health risk" from these kinds of substances.
    • Support of the committee's recent advice that a review into the scheduling of all surfactants (including this substance) should take place. Further consultation with industry is needed should a review take place.
    • This substance is not entered in the TGA eBS ingredients list, nor is it entered in the TGA Permitted Ingredients List. It is therefore assumed that the scheduling proposal will not impact therapeutic goods. Should any inadvertent impact be revealed, we would like to provide comment during the public consultation on the interim decision.

    The public submissions will be made available on the TGA website.

    Summary of ACCS advice to the delegate

    The committee recommended that the schedule 6 and index entries for the 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives be amended as follows:

    Schedule 6 – Amend Entry

    1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES except:

    1. In cosmetic rinse-off preparations containing 8 per cent or less of 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives when labelled with a warning statement to the following effect statement:
    2. IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or

    3. In household cleaning preparations, other than those intended to be sprayed, containing 1012 per cent or less of 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives when labelled with a warning statement to the following effect statement:
    4. IF IN EYES WASH OUT IMMEDIATELY WITH WATER.

    Index – Amend Entry

    1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES
    cross-reference: COCOYL METHYL GLUCAMIDE, LAUROYL METHYL GLUCAMIDE, MYRISTOYL METHYL GLUCAMIDE

    The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date. It should be noted that the new Schedule 6 entry for delegate’s final decision on 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives is to be implemented on 1 February 2018.

    Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the recommendation comprised the following:

    1. the risks and benefits of the use of a substance:
    • Risks: 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is a severe eye irritant and a skin irritant. This is a common hazard for all surfactants including soap and this hazard/risk is well understood by the public.
    • Benefits: surfactants as a group are useful, as they increase miscibility of hydrophilic and hydrophobic substances.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The applicant identified that 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives are potentially in widespread use in cosmetics and domestic (household cleaning) products.
  • the toxicity of a substance:
    • 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives are a severe eye irritant and skin irritant.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The current known formulations are up to 8% concentration in cosmetics and 12% in household cleaning products.
    • Currently, products with this chemical in the formulation would be labelled, packaged and presented appropriately for a cosmetic product or a household cleaning product, i.e. small packaging with use instructions as appropriate.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • The primary intent of the existing entry for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is to provide label directions that the eyes should be washed if the chemical gets in the eye. This has the effect of scheduling the chemical at any concentration in spray cleaners.
    • There is ongoing research with the aim to provide surfactants for use in cosmetics and household products that have the lowest possible irritancy and sensitising potential in order to improve public health protection and ecological impact.
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    • Scheduling proposal
    • ACCS advice
    • Public submissions received
    • Section 52E of the Therapeutic Goods Act 1989
    • Scheduling Policy Framework (SPF 2015)
    Delegate's interim decision

    The delegate's interim decision is to not specifically list 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives as it is captured by the Schedule 6 entry for 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives, which is to be implemented on 1 February 2018, and to amend the 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives by removing "coco" to capture similar substances. The proposed schedule entry is:

    Schedule 6 – Amend Entry

    1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N- ACYL DERIVATIVES except:

    1. in cosmetic rinse-off preparations containing 8 per cent or less of 1-deoxy-1-(methylamino)-D-glucitol N- acyl derivatives when labelled with a warning statement to the following effect:
    2. IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or

    3. in household cleaning preparations, other than those intended to be sprayed, containing 12 per cent or less of 1-deoxy-1-(methylamino)-D-glucitol N- acyl derivatives when labelled with a warning statement to the following effect:
    4. IF IN EYES WASH OUT IMMEDIATELY WITH WATER.

    Index – Amend Entry

    1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-ACYL DERIVATIVES
    cross-reference: COCOYL METHYL GLUCAMIDE, LAUROYL METHYL GLUCAMIDE, MYRISTOYL METHYL GLUCAMIDE

    The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

    The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risks: 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is a severe eye irritant and a skin irritant. This is a common hazard for all surfactants including soap and this hazard/risk is well understood by the public.
    • Benefits: surfactants as a group are useful, as they increase miscibility of hydrophilic and hydrophobic substances.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The applicant identified that 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives are potentially in widespread use in cosmetics and domestic (household cleaning) products.
  • the toxicity of a substance:
    • 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives are a severe eye irritant and skin irritant.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The current known formulations are up to 8% concentration in cosmetics and 12% in household cleaning products.
    • Currently, products with this chemical in the formulation would be labelled, packaged and presented appropriately for a cosmetic product or a household cleaning product, i.e. small packaging with use instructions as appropriate.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • The primary intent of the existing entry for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is to provide label directions that the eyes should be washed if the chemical gets in the eye. This has the effect of scheduling the chemical at any concentration in spray cleaners.
    • There is ongoing research with the aim to provide surfactants for use in cosmetics and household products that have the lowest possible irritancy and sensitising potential in order to improve public health protection and ecological impact.

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